# Peripheral mechanisms of central neuropathic pain in multiple sclerosis

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $66,390

## Abstract

Nguyen, Kayla
PROJECT SUMMARY/ABSTRACT
Neuropathic Pain (NP) afflicts over 50% of patients with multiple sclerosis (MS), yet current treatments for pain
relief are inadequate, in part because mechanisms that drive MS pain are poorly understood. In a widely-used
animal model of MS, experimental autoimmune encephalomyelitis (EAE), recent electrophysiological recordings
of primary afferent neurons (PANs) in the dorsal root ganglion (DRG) revealed: 1) hyperexcitability of medium-
to-large diameter neurons and 2) an increase in afterhyperpolarization of small-diameter fibers. These data
provide the premise for my long-term goal to investigate the sensitization mechanisms at PANs that drive NP in
the EAE model. With behavioral, transgenic, and ablation techniques, I propose to assess the contribution of A
and C-fibers to MS pain upon testing the overall hypothesis that EAE produces a persistent hyperexcitability of
A and/or C-nociceptors (Aim 1,2) that is associated with increased activity of dorsal horn (DH) neurons (Aim 3)
that then drives NP. Aim 1 uses neuronal ablation strategies to identify which subpopulations of primary afferent
neurons contribute to NP in EAE. I will use simple conventional neuronal ablation strategies (neonatal capsaicin,
intrathecal capsaicin, intrathecal IB4-saporin, intraplantar flagellin/QX-314), followed by a more labor-intensive
but powerful conditional knockout approach to eliminate the activity of increasingly precise PAN subsets. I predict
that the proposed interventions will reduce key indicators of EAE-induced pain: mechanical and cold
hypersensitivity (reflexive pain) and conditioned place aversion (affective pain). Aim 2 uses chemogenetics and
optogenetics to test the hypothesis that either Mrgprd- or TrkC-expressing PANs are necessary for NP in EAE.
I predict that CreER selective manipulations to inhibit either the MrgprD+ subset of IB4 neurons or the TrkC+
subset of myelinated neurons (decision driven by the results of Aim 1a-b) will reduce EAE mechanical and cold
hypersensitivity. Aim 3 will test the hypothesis that EAE sensitizes the somatosensory stimulus-induced
activation of spinal interneurons and projection neurons. Our laboratory reported that EAE increases the activity
of dorsal horn neurons as measured by the expression of pERK. I propose to extend these studies with a more
powerful measure of neuronal activity using spinal cord slice Fura-2 calcium imaging, and by assessing the
activity not only of interneurons, but also of projection neurons. The Pittsburgh Center for Pain Research will
provide guidance, support, and learning opportunities that will promote the development of my scientific and
investigative career aspirations.

## Key facts

- **NIH application ID:** 10285258
- **Project number:** 1F32NS118101-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kayla Lee Nguyen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 1
- **Project period:** 2021-08-15 → 2023-01-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285258

## Citation

> US National Institutes of Health, RePORTER application 10285258, Peripheral mechanisms of central neuropathic pain in multiple sclerosis (1F32NS118101-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10285258. Licensed CC0.

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